Cardiome Pharma Corp. laid out a strategy to begin a Phase III program for RSD1235, its homegrown anti-arrhythmic product.
Scheduled to begin in the second half of the year, the first of three Phase III trials will study an intravenous application of RSD1235 in about 350 atrial fibrillation patients. The cohort primarily includes new-onset patients - those with atrial fibrillation for less than seven days - in whom efficacy in slowing the heart's rhythm back to normal levels will be evaluated as the trial's primary endpoint. The compound's safety in longer-duration patients will be studied as well.
The remaining two trials will be conducted in parallel and Cardiome expects the entire program to last less than three years.
"At our end-of-Phase II meeting with the FDA, we proposed to study RSD1235's efficacy and safety in 1,000 patients," Alan Ezrin, Cardiome's chief scientific officer, told BioWorld Today. "The goal is to demonstrate that it can add value to this therapy different than any other therapy that's out there, with its very rapid onset and high level of activity."
Invented and developed at Vancouver, British Columbia-based Cardiome, the treatment is designed to selectively block ion channels in the heart known to be active during atrial fibrillation episodes.
The first trial's design replicates that of a Phase II trial on which Cardiome reported late last summer. Data from the study of 56 new-onset patients showed that RSD1235 terminated atrial fibrillation in 61 percent of patients vs. 5 percent of placebo within 30 minutes of the end of infusion (p=0.0003).
The last trial will follow that same design, while the middle study will evaluate the compound in a surgical patient population who have undergone bypass grafting. Both will include about 350 patients tested with an intravenous formulation.
Cardiome noted that no significant drug-related adverse events have been reported in patients exposed to RSD1235 to date, while other acute treatment drugs produce safety issues ranging from drug-induced proarrhythmia to other cardiac liabilities. Given the body of evidence to support the product, Cardiome has high hopes for RSD1235 and expects to carry its development forward with a commercial partner. (See BioWorld Today, Sept. 4, 2002.)
"We have a very robust clinical plan laid out," Ezrin said. "We are very enthusiastic about moving forward in conjunction with being able to partner this. Our major objective is to bring in a multinational pharmaceutical company to partner and co-develop this drug effectively and get it to NDA registration in less than three years."
He said potential partners that specialize in cardiovascular and arrhythmia sales are aware of Cardiome and its program, noting that a deal could be reached by the end of the year. Ezrin added that finalizing RSD1235's development through a partnership would free up capital for additional late-stage programs.
A next-generation oral formulation of the compound is being developed for disease prevention rather than treatment. Data have shown that blood levels of the orally administered version reached concentrations equivalent to the doses of RSD1235 seen in the Phase II study.
Beyond the compound, Cardiome has advanced another drug into pivotal trials. In March it began patient dosing with oxypurinol in a Phase II/III study of congestive heart failure patients. The 400-patient trial will assign doses of oral oxypurinol or placebo for six months. Oxypurinol, which belongs to a class of drugs that increases the pumping action of the heart without a proportionate increase in oxygen consumption by the organ, will be administered in addition to standard medications.
"This trial is looking to demonstrate that over a six-month course of therapy, clinical outcomes such as death, rehospitalization and a need for intervention of heart failure are reduced by oral daily dosing of oxypurinol," Ezrin said.
Cardiome gained rights to the compound last year in a merger with New York-based Paralex Inc. Through the deal, Cardiome acquired a license to all intellectual property related to xanthine oxidase inhibitors used for managing congestive heart failure and has expanded the patent portfolio to include all cardiovascular diseases. The license came from Johns Hopkins University in Baltimore. At the same time, the company completed a public offering of about 37.2 million shares priced at C83 cents each, raising about US$19.5 million. (See BioWorld Today, March 12, 2002.)
Cardiome also has plans to develop oxypurinol as an orphan indication in gout for patients intolerant to allopurinol, the first-line therapy for the condition. The compound is the primary metabolite of allopurinol. Ezrin said the new drug application process is under way.
Still in preclinical development at Cardiome is a late-stage research program targeting an ion channel called KV1.5. The company is exploiting the program to develop an arrhythmia control compound to prevent atrial fibrillation. Ezrin said blockers of the ion channel, which allows potassium to move in and out of heart cells, are thought to be found only in the atria. Cardiome has found that affecting the channels modulates the function of the atria and is looking to partner the program as well.
"We don't know of many specialty franchises in cardiovascular medicine, but that's the area we have staked out," Ezrin said. "It's been a tough couple of years for the sector as a whole, but we have done very well."
Cardiome's stock (OTCBB:COMRF) gained 11 cents Wednesday to close at $1.98.